Both HLA class II and class III DNA polymorphisms are linked to juvenile rheumatoid arthritis susceptibility

doi:10.1016/0090-1229(90)90165-M

Clinical Immunology and Immunopathology

Volume 56, Issue 1, July 1990, Pages 22-28

Clinical Immunology ...

https://doi.org/10.1016/0090-1229(90)90165-M Get rights and content

Abstract

HLA-DR5 and DRw8 are not significantly linked to juvenile rheumatoid arthritis (JRA) in the Spanish population. However, we have found restriction fragment length polymorphisms (RFLPs) βDR-2.9-kb-EcoRI and C4-14.3-kb-EcoRI, that correlate significantly with JRA. Eighty-six percent of our patients present either HLA-DR5 or the βDR-2.9-kb-EcoRI allogenotope or lack the C4-14.3-kb-EcoRI allogenotope compared to 48% in controls; however, these particular DR and C4 RFLPs may not represent the corresponding DRB1 or C4 genes but rather neighboring ones which may be relevant to confer JRA susceptibility. The C4-14.3-kb-EcoRI RFLP decrease in patients may reflect a decrease in C4 B “long” phenotypes. Also, both RFLPs are the only markers able to identify most of the JRA patients in our population. On the other hand, the findings of both class II and III genes associated to JRA may reflect the existence of epistatic interactions (cis or trans) within the HLA gene cluster which lead to a particular pathology in certain diseases.

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Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthropathy of childhood. Juvenile idiopathic arthritis is believed to be a complex genetic trait influenced by both genetic and environmental factors. Twin and family studies suggest a substantial role for genetic factors in the predisposition to JIA. Describing the genetics is complicated by the heterogeneity of JIA; the International League of Associations for Rheumatology (ILAR) has defined seven categories of JIA based on distinct clinical and laboratory features. Utilizing a variety of techniques including candidate gene studies, the use of genotyping arrays such as Immunochip, and genome wide association studies (GWAS), both human leukocyte antigen (HLA) and non-HLA susceptibility loci associated with JIA have been described. Several of these polymorphisms (e.g. HLA class II, PTPN22, STAT4) are shared with other common autoimmune conditions; other novel polymorphisms that have been identified may be unique to JIA.
Associations with oligoarticular and RF-negative polyarticular JIA are the best characterized. A strong association between HLA DRB1:11:03/04 and DRB1:08:01, and a protective effect of DRB1:15:01 have been described. HLA DPB1:02:01 has also been associated with oligoarticular and RF-negative polyarticular JIA. Besides PTPN22, STAT4 and PTPN2 variants, IL2, IL2RA, IL2RB, as well as IL6 and IL6R loci also harbor variants associated with oligoarticular and RF-negative polyarticular JIA. RF-positive polyarticular JIA is associated with many of the shared epitope encoding HLA DRB1 alleles, as well as PTPN22, STAT4 and TNFAIP3 variants. ERA is associated with HLA B27. Most other associations between JIA categories and HLA or non-HLA variants need confirmation. The formation of International Consortia to ascertain and analyze large cohorts of JIA categories, validation of reported findings in independent cohorts, and functional studies will enhance our understanding of the genetic underpinnings of JIA.
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Regular articleBoth HLA class II and class III DNA polymorphisms are linked to juvenile rheumatoid arthritis susceptibility

Abstract

Lancet

J. Mol. Biol.

Mol. Immunol.

Amer. J. Med.

Juvenile chronic arthritis, pauciarticular type

Inherited predisposition to iridocyclitis with JRA: Selectivity among HLA-DR5 haplotypes

DR, C4, and Bf allotypes in juvenile rheumatoid arthritis

Arthritis Rheum.

HLA antigens in a sample of the Spanish Population: Common features among Spaniards, Basques and Sardinians

Hum. Genet.

New methods for detection of HLA genes polymorphism useful for associated diseases studies

Pathol. Biol.

New HLA DNA polymorphisms associated with autoimmune diseases

Nature (London)

A systemic study of HLA class II DNA restriction fragments in insulin dependent diabetes mellitus (IDDM)

DNA typing of HLA-DR antigens in systemic lupus erythematosus

Immunogenetics

Current proposed revision of JRA criteria

Arthritis Rheum.

Serotyping for homotransplantation. XVIII. Refinement of microdroplet lymphocyte cytotoxicity test

Transplantation

Regular article
Both HLA class II and class III DNA polymorphisms are linked to juvenile rheumatoid arthritis susceptibility